1. Field of the Invention
The invention is directed to novel biological compounds. More particularly the present invention relates to MyD88 Adapter-Like-1 (MAL-1) DNA, polypeptides encoded by the DNA, processes for producing the polypeptides, antibodies specific to the polypeptides and uses thereof.
2. Description of Related Art
The Interleukin-1 (IL-1) pathway is a cellular signaling pathway is that plays a crucial role in the mammalian inflammatory response. Several different receptors and ligands are involved in this pathway, including the ligands IL-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1ra), and two IL-1 receptors referred to as IL-1 receptor Type I (IL-1RI) and IL-1 receptor Type II (IL-1RII); a soluble form of the latter also exists. Of these, it appears that IL-1LRI is the signaling receptor, whereas IL-1RII does not transduce signal to a cell, but instead may be involved in regulating an IL-1-mediated response (Colotta et al., Immunol. Today 15:562; 1994).
Signaling via the IL-1 pathway is complex, requiring a number of accessory molecules in addition to IL-1RI, including a receptor-associated kinase and an adapter molecule. Formation of the receptor complex leads to the activation of Nuclear Factor kappa B (NFkappaB), a transcription factor central to the regulation of an inflammatory response. Toll-like receptors (TLRs) belong to a superfamily of proteins which contain the Toll 1L-1 receptor domain (TIR). The 10 Toll-like receptors in the human genome recognize microbial products during innate immunity and signal through their TIR. A TLR-4 homodimer signals during the immune response to LPS.
MyD88 is an adapter molecule associated with the IL-1R signaling complex that was originally identified in murine myeloleukemic cells. It has areas of homology with both the IL-1R signaling domain and with the so-called death domains found in Tumor Necrosis Receptor (TNFR) family members (Bonnert et al., FEBS Letters 402:81; 1997).
Signaling by TLRs also employs MyD88 and induces activation of NF-κB via the kinase IRAK, similar to IL-1R-mediated NF-κB activation. MyD88 is a cytoplasmic TIR domain-containing protein and also contains an N-terminal death domain. Both the death domain and TIR domain of MyD88 recruit the IL-1 receptor associated Kinase (IRAK) and IRAK-2 during signal transduction. Like the TLRs, IL-1R signals through MyD88 and utilizes MyD88 to recruit the kinases IRAK1 and IRAK2.
IL-1 has been implicated in a variety of diseases and conditions, including rheumatoid arthritis, multiple myeloma, osteoporosis, endotoxemia and sepsis, osteoarthritis, inflammatory bowel disease and allergy. Inhibition of the signaling of IL-1 using soluble forms of IL-1Rs, and the IL-1ra, have been shown to be useful in treating or ameliorating disease characterized by excess levels of IL-1 (Bresnihan et al., Arthritis Rheum. 41:2196, 1998; Bresnihan et al., Ann. Rheum. Dis. 58 Suppl. 1:196, 1999; Bendele et al., Arthritis Rheum. 42:498, 1999; van den Berg et al., Clin. Exp. Rheumatol. 17 Suppl. 18:S105, 1999; Joosten et al., J. Immunol. 163:5049, 1999). Other parts of the IL-1 signaling pathway have also been the target of attempts to identify additional molecules that can be used therapeutically to intervene in conditions related to IL-1. Thus, there is a need in the art to identify novel molecules involved in the IL-1 signaling pathway, both as tools with which to investigate cell signaling and for use in identifying inhibitors of IL-1 signaling.